New hormonal composition and its use

ABSTRACT

A method of preventing estrogen deficiencies and osteoporosis in menopausal women by continuously orally administering without interruption to menopausal women in need thereof an amount of 0.3 to 3 mg of 17β-estradiol or esters thereof and 0.3 to 1.25 mg of nomegestrol or esters thereof in an amount sufficient to prevent said problems.

SUMMARY OF THE TECHNICAL CONTENT OF THE INVENTION

The present invention relates to the field of therapeutic chemistry andmore particularly to the field of pharmaceutical hormonal technique.

More precisely, its subjects are new pharmaceutical hormonalcompositions formed of an estrogen-progestative association consistingof an estrogen compound and a progestative compound, in combination oradmixed with one or more non-toxic, inert pharmaceutically-acceptablediluents suitable for oral administration.

The present invention also concerns the use of the estrogen-progestativemixture in which the estrogen compound and the progestative compound areadministered in combination. The combined association may be prescribedcontinuously or discontinuously, with a view to produce a compositiondesigned to treat estrogen deficiencies and to prevent osteoporosis andcardiovascular disorders in menopausal women.

A further object of the invention is a process for the preparation ofthe said new pharmaceutical estrogen-progestative compositions.

New Hormone Composition and its Use

The present invention relates to the field of therapeutic chemistry andmore particularly to the field of pharmaceutical hormonal technique.

More precisely, its subjects are new pharmaceutical compositions formedof an estrogen-progestative association designed to correct estrogendeficiencies in women, regardless of their origin, and more particularlyin menopausal women.

In particular its objective is an estrogen-progestative associationcharacterised in that it consists of dose units containing a combinationof a progestative and an estrogen, both compounds being present at thesame time in each medicinal dose.

Specifically, its subjects are new pharmaceutical compositions intendedfor hormone replacement therapy in menopause, which contain as activeingredient a progestational agent chosen from among nomegestrol and itsesters and an estrogen agent chosen from among estradiol and its estersand the conjugated equine estrogens.

This association is intended for administration via the oral route, beit continuously or discontinuously.

As is known, over the course of less than a century the life expectancyof women has increased from 50 to 80 years, while the mean age at whichthe menopause begins has remained unchanged. Thus, women spend almostone-third of their life in a condition of estrogen deficiency, and thisresults in a higher risk of osteoporosis and cardiovascular disorders.Replacement therapy for the menopause has therefore become verywidespread. It is administered either orally or, at least as regards itsestrogen component, via the percutaneous route. Nevertheless, complianceseems better when the treatment is administered orally (ETTINGER et al.,1998).

Consecutive replacement therapy in the menopause cures thesymptomatology of the climacteric.

It prevents osteoporosis and the onset of cardiovascular disorders. Itcreates artificial cycles which are followed by deprivational bleeding.This therapeutic scheme is particularly well suited to women whosemenopause is recent, but it is not always well accepted in the longterm, which partly explains the poor compliance with the treatment(DRAPIER FAURE E., Gynecology, 1992, 43: 271-280).

To overcome this drawback combined associations have been developed inwhich the two components are taken simultaneously, whether continuouslyor discontinuously, the effect of the progestative being to permanentlyoppose the proliferative action of the estrogen upon the endometrium, soinducing an atrophy of the endometrium and consequently preventingdeprivation bleeding (HARGROVE J. T., MAXSON W. S., WENTZ A. C., BURNETTL. S., Obstet. Gynecol., 1989, 73: 606-612). In fact, under theseconditions the endometrial atrophy is pronounced (WOLFE and PLUNKETT,1994; PIEGSA et al., 1997; AFFINITO et al., 1998), there is noendometrial hyperplasia (STADBERG et al., 1996) and the frequency ofbleeding is low and decreases with time (PIESGA et al., 1997;CARRANZA-LIRA, 1998; ETTINGER et al., 1998). With this type oftreatment, compliance is generally good (EIKEN and KULTHOFF, 1995; DORENet al., 1996), and certainly better than with consecutive treatment(EIKEN et al., 1996). The quality of life too seems improved (ULRICH etal., 1997). It is also known that this type of treatment protects thebone mass (EIKEN et al., 1996; EIKEN et al., 1997; HART et al., 1998;RECKER et al., 1999).

This “no-periods” scheme is particularly well suited for women whosemenopause occurred already some time ago. Consecutive associations canbe prescribed subsequently in order to improve long-term compliance withhormone replacement therapy in the menopause.

During consecutive treatments the progestative dose chosen is thatwhich, in the long term, leads to at least 1% of endometrial hyperplasiawhen the progestative is administered discontinuously for more than 10days per cycle in menopausal women undergoing estrogen replacementtherapy (WHITEHEAD et al., J. Reprod. Med., 1982, 27: 539-548; PATERSONet al., Br. Med. J., 1980, 22 Mar.: 822-824).

The progestative dose to be used in a combined replacement therapy isgenerally lower than that normally prescribed in consecutive schemes.Examples are micronised progesterone, dydrogesterone (FOX H., BAAK J.,VAN DE WEIJER P., AL-AZZAWI E., PATERSON M., JOHNSON A., MICHELL G.,BARLOW D., FRANCIS R., 7th International Congress on the Menopause,Stockholm, 20-24 Jun. 1993, abstr. 119) and medroxyprogesterone acetate(BOCANERA R., BEN J., COFONE M., GUINLE I., MAILAND D., SOSA M., POUDESG., ROBERTI A., BISO T., EZPELETA D., PUCHE R., TOZZINI R., 7thInternational Congress on the Menopause, Stockholm, 20-24 Jun. 1993,abstr. 40), which have been used respectively at doses of 100, 10 and 5mg/day with encouraging results at the clinical and endometrial level.

Combined treatment is most often used continuously i.e. withoutinterruption. Some, however, prefer to use it intermittently, forexample on 25 days each month (BIRKAUSER M., et al.; Hormonesubstitution: a well defined indication and individual treatment schemesare decisive for the success of the therapy, Med. & Hyg., 1995, 53:1770-1773). The purpose of interrupting the treatment is to remove theinhibition by the progestative of the synthesis of estradiol andprogesterone receptors and so to avoid reducing the receptivity of thehormone-dependent tissues.

The progestative used according to the present invention is nomegestrolor one of its esters, mainly nomegestrol acetate. Nomegestrol acetate isa powerful progestative which is active via the oral route and has anoriginal pharmacological profile:

-   -   in contrast to the derivatives of 19-nortestosterone,        nomegestrol acetate shows no residual androgenic and estrogenic        action;    -   in common with the derivatives of 17-alpha-hydroxyprogesterone        it has a pure pharmacological profile, but in contrast to them        it has a powerful antigonadotropic action.

It belongs to the category of qualified hybrid progestatives (OETTEL etal., 1999), which have no harmful metabolic effects because of theabsence of a 17-alpha-ethinyl function, and which combine the advantagesof the progesterone derivatives with those of the most modern among the19-nortestosterone derivatives.

Its use in consecutive administration during the menopause at a dose of5 mg/day for 12 days per cycle, in association with various types ofestrogens, makes it possible to prevent endometrial hyperplasia as hasbeen shown by a multicentric trial in 150 women over 1 year (THOMAS J.L., BERNARD A. M., DENIS C., 7th International Congress on theMenopause, Stockholm, 20-24 Jun. 1993, abstr. 372).

The absence of hyperplasia was confirmed in a study in which nomegestrolacetate was administered at the same dose for 14 days per cycle to womenbeing treated with percutaneous estradiol (BERNARD A. M. et al.,Comparative evaluation of two percutaneous estradiol gels in combinationwith nomegestrol acetate in hormone replacement therapy. XIV WorldCongress of Gynecology and Obstetrics, FIGO, Montreal, 24-30 Sep. 1994).This utilisation, which is covered by French Patent No. 2.737.411 in thename of the Applicant Company, claims a dose range from 1.5 to 6 mg andpreferably from 2.5 to 5 mg.

The estrogen used is estradiol, free or esterified, and in particularestradiol valerate, or the conjugated equine estrogens, presented in aformulation that is active via the oral route. It has been shown that anestradiol dose of between 1 and 2 mg/day is enough to combat theestrogen deficiency in menopausal women.

The nomegestrol acetate and free or esterified estradiol, or theconjugated equine estrogens are administered in one of the forms that issuitable for oral administration: gelatine capsules, capsules, pills,powder sachets, tablets, coated tablets, sweetened tablets, etc.

The present invention is characterised by the fact that it is a newestrogen-progestative association which is active via the oral route,and is administered in combination. A further object of this inventionis the use of compositions according to the invention to correctestrogen deficiencies and to prevent osteoporosis and cardiovasculardisorders in menopausal women.

The present invention is also defined by:

a) The Fact that the Estrogen-Progestative Association Concerned isDifferent from Those Described Before Now for the Same Type ofIndications.

Certain patents claim the continuous use of estrogen-progestativecombinations for replacement therapy in menopause. Examples are thepatents U.S. Pat. No. 5,108,995 or EP 309263. It is evident, however,that these patents claim multisequential treatments with dose changes ofthe active ingredients. This is also true of the patents filed in theUSA (U.S. Pat. No. 4,820,831A) and in Europe (EP 136 011) in the name ofPLUNKETT. Those patents claim the use of numerous estrogens and numerousprogestatives in menopause replacement therapy. It seems, however, thatthe said claims do not cover the use of all progestatives, on the onehand for scientific reasons and on the other hand for scientific andlegal reasons related to the wording of the claims of the two saidpatents:

-   -   1) The use of numerous progestatives is based on equivalences        with one of them, in this case levonorgestrel. This approach        seems unacceptable because different progestatives have very        different pharmacological profiles and the doses to be used        cannot be deduced from a simple and unique equivalence system,        as becomes clear from the active dose ranges proposed for        different progestatives in 3 different patents (Table 1).

It can be seen that the lower limit for the various progestatives variesin a ratio of 2.4 to 50 while the maximum dose varies in a ratio of 1 to50. Thus, for indications of the same type, the dose range varies veryconsiderably from one patent to the next and this shows that the systemof equivalence does not lend credibility to the relationship which couldbe established between progestatives.

-   -   2) Apart from the above, it would be reasonable to think that        the doses claimed should be based on data from clinical        pharmacology and/or clinical data previously published and        commonly accepted. Now, if the doses defined as in the PLUNKETT        patents are considered, it is easy to see that in most cases the        active doses published already a long time ago, i.e. before the        said patents were filed (NEUMANN, 1977) or more recently (KUHL,        1996), are very coherent but only rarely lie within the dose        ranges claimed in the patents in the name of PLUNKETT (Table 2).

This finding is also valid if, instead of the active doses as above,account is taken of the active dose ratios given by taking norgestrel asreference (=1) (Table 3).

TABLE NO. 1 Doses (μg/day) of the various progestatives claimedaccording to the patents DOSE (μg/day) PROGESTATIVE PATENT MinimumMaximum Levonorgestrel WO 95/17194  60 125 Levonorgestrel EP 025607 A1 25 100 Levonorgestrel PLUNKETT  25  75 Gestodene WO 95/17194  50  75Gestodene EP 025607 A1  10  70 Desogestrel WO 95/17194  60 150Desogestrel EP 025607 A1  25 100 3-ketodesogestrel WO 95/17194  60 1503-ketodesogestrel EP 025607 A1  25 100 Norethisterone WP 95/17194 350750 Norethisterone EP 025607 A1  85 350 Norethisterone PLUNKETT 150 1000   Norethisterone acetate PLUNKETT 100 1 000   Norgestimate WO95/17194 200 300 Norgestrel PLUNKETT  50 150 Ethynodiol diacetatePLUNKETT 100 1 000   Dihydrogesterone PLUNKETT 5 000   30 000   MPAPLUNKETT 1 000   15 000   Norethynodrel PLUNKETT 200 5 000  Allylestrenol PLUNKETT 1 000   10 000   Lynoestrenol PLUNKETT 100 2000   Quingestanol acetate PLUNKETT  50 1 000   Medrogestone PLUNKETT 1000   10 000   Norgestrienone PLUNKETT  20 200 Dimethisterone PLUNKETT500 15 000   Ethisterone PLUNKETT 1 000   25 000   Cyproterone acetatePLUNKETT 100 10 000   Cyproterone acetate WO 95/17194 100 200

TABLE NO. 2 Doses of each progestative according to the variousbibliographical references NEUMANN PUBLICATION KUHL U.S. Pat. No.4,826,831 Endometrium Menstruation Ovulation Contraception EndometriumOvulation Min. Max. (1) (2) (3) (4) (1) (3) Levonorgestrel 25 75 400 60Norgestrel 50 150 1200 2000 100 250 Norethisterone 150 1000 12500 5000800 1000 10000 400 Norethisterone acetate 100 1000 4500 800 1000Ethynodiol diacetate 100 1000 Dydrogesterone 5000 30000 MPA 1000 150005500 25000 5000 Norethynodrel 200 5000 10000 7500 6000 2500Allylestrenol 1000 10000 1750 Lynoestrenol 100 2000 5000 2500Quingestanol acetate 50 1000 Medrogestone 1000 10000 Norgestrienone 20200 Dimethisterone 500 15000 Ethisterone 1000 25000 CIP acetate 10010000 1000 1000 2000 2000 1000 The cases appearing in bold abovecorrespond to active doses outside the dose ranges claimed in the“PLUNKETT” patents. The doses (μg/day) are those necessary to inducetransformation of the endometrium (1), to produce an adequate delay inthe onset of periods (2), to inhibit ovulation (3), or to have acontraceptive effect (4).

TABLE NO. 3 Dose ratios of each progestative according to the variousbibliographical references The reference progestative is norgestrel (=1)NEUMANN U.S. Pat. No. 4,826,831 Ratios Ratios Endometrium OvulationMenstruation Contraception Min. Max. (1) (3) (2) (4) Levonorgestrel 0.50.5 Norgestrel 1.0 1.0 1.0  1.0 1.0 1.0 Norethisterone 3.0 6.7

4.0 Norethisterone acetate 2.0 6.7 3.8

4.0 Ethynodiol diacetate 2.0 6.7 Dydrogesterone 100.0 200.0 MPA 20.0100.0

20.0 Norethynodrel 4.0 33.3 8.3

10.0 Allylestrenol 20.0 66.7

Lynoestrenol 2.0 13.3 4.2 10.0 Quingestanol acetate 1.0 6.7 Medrogestone20.0 66.7 Norgestrienone 0.4 1.3 Dimethisterone 10.0 100.0 Ethisterone20.0 166.7 CIP acetate 2.0 66.7

10.0 8.0 The cases appearing in bold and Italics correspond to activedoses outside the ratio ranges claimed in the US and EP patents cited inthe name of PLUNKETT. For the meanings of (1), (2), (3) and (4), seeTable 2.

Reasoning Related to the Claims

1) In the US patent cited above, claims 1 and 2 relate to continuoustreatments; the only progestatives claimed are dl-norgestrel andlevonorgestrel. The subsequent claims concern discontinuousmultisequential treatment, i.e. a therapeutic scheme different from thatproposed in the present patent application. For this latter type oftherapeutic regime the number of progestatives claimed is larger but thelist thereof is precise and limited, as emerges from the Markush-typepresentation of the said claims, and it does not include nomegestrol andits esters.

2) The European patent only claims the continuous combined treatment;the estrogens and progestatives claimed are listed in tables present inthe body of the text and summarised in the claims. There too,nomegestrol and its esters do not feature in the lists of progestativesthat can be used. Now, nomegestrol acetate is characterised by apowerful progestational action, an absence of residual androgenic andestrogenic effects, and a powerful anti-estrogenic action which ismanifested at the level of the endometrium by marked anti-mitoticactivity and, consequently, a pronounced atrophying effect. Accordingly,it cannot be likened to the other progestatives and to think in terms ofa dose correspondence relative to another progestative taken asreference cannot but be erroneous. Moreover, nomegestrol acetate ischaracterised by excellent tolerance; it has no effect on the lipidsprofile, the tolerance to glucides, the arterial pressure and thecoagulation factors, even when used at doses higher than those describedin the present patent application and in prolonged treatments (BASDEVANTet al., 1997). This aspect is very important because all therapists incommon strive to use the treatment with least possible toxicityinvolving the lowest possible doses. In this respect, nomegestrolacetate differs from many derivatives of 19-nortestosterone cited in thePLUNKETT patents, which are progestatives characterised by androgenicand estrogenic effects which can have consequences at the level of theendometrium and which also have harmful metabolic effects.

For the same reasons as those mentioned above, none of the numerouspublications that deal with the continuous combined treatment of themenopause can have a bearing on the present invention because none ofthese publications deals with an association of nomegestrol acetate withan estrogen. This for example applies to associations of estradiol andnorethisterone acetate (STADBERG et al., 1996; DOREN and SCHNEIDER,1996; DOREN et al., 1997; EIKEN et al., 1997; PIEGSA et al., 1997; HARTet al., 1998), estradiol and medrogestone (AFFINITO et al., 1998),estradiol and norgestrel (WOLFE and PLUNKETT, 1994), estradiolvalerianate and chlormadinone acetate (RAUCH and TAUBERT, 1993), andconjugated equine estrogens with medroxyprogesterone acetate (REUBINOFFet al., 1995; WOLFE and HUFF, 1995; MIZUNUMA et al., 1997) ormedrogestone (RECKER et al., 1999).

b) The Fact that this Estrogen-Progestative Association is Differentfrom the Association Previously Patented by the Applicant.

In effect, French Patent No. 2.754.179 in the name of the Applicantclaimed an association of estradiol and nomegestrol acetate for thecombined replacement therapy of the menopause. The dose range claimed onthe basis of previous experience with nomegestrol acetate in consecutivetherapy was from 1.5 to 3.75 mg, preferably 2.5 mg. Now, clinical trialson a broader scale have shown that in an unexpected way, very much lowerdoses of nomegestrol acetate can induce endometrial atrophy with verygood control of bleeding. This observation is important because itallows the nomegestrol acetate doses to be reduced still further, sothat it can be used with still greater safety. The doses of Estradiolclaimed in this patent ranged from 0.5 to 3 mg. The same doses ofEstradiol are used but the ratio estrogen/progestative appears to bemarkedly altered 1:5 instead of 6:1.

c) Appropriate Production Method for the Pharmaceutical Forms

The invention concerns a production method with which the two activeingredients can be combined in one and the same pharmaceutical form.

The compositions according to the invention, based on nomegestrolacetate and free or esterified estradiol or conjugated equine estrogens,are administered either continuously or intermittently (from 21 to 28days per month).

According to a particular embodiment of the invention, the compositionscontain a quantity of nomegestrol acetate ranging from 0.3 to 1.5 mg anda quantity of free or esterified estradiol or conjugated equineestrogens ranging from 0.3 to 3 mg. Preferably, the optimum formulationscontain 0.625 to 1.25 mg of nomegestrol acetate associated with 0.5 to1.5 mg of free estradiol or 1.5 to 2 mg of estradiol ester or 0.312 to0.625 mg of conjugated equine estrogens, in each daily dose.

This mode of combined administration is indicated in menopausal women,whether the menopause is natural or the result of surgery; theestrogen-progestative combination is intended to compensate thefunctional disturbances induced by the menopausal estrogen deficiency,while maintaining endometrial atrophy and avoiding the appearance ofdeprivation bleeding in most of the women.

A further objective of the present invention is a process for obtainingnew pharmaceutical compositions, which consists in mixing the activeingredients: nomegestrol acetate and free or esterified estradiol orconjugated equine estrogens, with one or more inert, non-toxic andpharmaceutically acceptable diluents or vehicles.

Among the excipients may be mentioned binding and dissolution-promotingagents, compaction agents, disintegration agents and slip-promotingagents.

The said mixture is compacted directly or in several stages to formtablets which can be protected on the surface, if desired, with a film,a coating, or by being made into (knees. The production of tablets bydirect compaction makes possible the maximum reduction of the proportionof dilution agents, binding agents, disintegration agents andslip-promoting agents.

Soft gelatine capsules can be produced by mixing the active ingredientswith an inert diluent and with a sliding agent.

The tablets contain, in particular, agents which dilute the mass such aslactose, sorbitol for direct compaction, as marketed under the nameNEOSORB 60, Palatinite which is the registered trademark designating anequimolar mixture of isomer of [D]glucopyranosido-1,6-mannitol and[D]glucopyranosido-1,6-glucitol crystallised with two water molecules,mannitol, sorbitol, or the lactose/PVP mixture marketed under the nameLudipress.

The compaction binding agents are generally microcrystalline cellulosessuch as those marketed under the name AVICEL PH 101 or AVICEL PH 102.Polyvinylpyrrolidone also plays an important part by facilitating theagglomeration of the powders and the compressibility of the mass. Thepolyvinylpyrrolidones used for this purpose have molecular weightsbetween 10000 and 30000, such as Povidone, or Kollidon graded from 12 to30.

The mixture also contains slip-gliding or anti-electrostatic agentswhich prevent the powder from agglomerating in the feed hoppers. In thisconnection the colloidal silicas marketed under the name AEROSIL, 100 orAEROSIL 200 may be mentioned.

The mixture also contains disintegration agents which make fordisintegration or crumbling in accordance with pharmaceutical standards.As useful disintegration agents it may be mentioned the cross-linkedvinylpyrrolidone polymers such as those marketed under the namesPolyplasdone or Polyclar AT, carboxymethyl starches such as thosemarketed under the names Amijel or Explotab, or cross-linkedcarboxymethyl celluloses such as the compound sold under the nameAC-DI-SOL.

In addition, the preparation contains lubricant agents which facilitatecompaction and the ejection of the tablet from the tableting machines.As lubricants it may be mentioned glycerol palmitostearate as sold underthe name Precirol, magnesium stearate, stearic acid or talc.

After compaction the tablets can be coated to improve their storageproperties or to facilitate swallowing.

The coating agents are either cellulosic, such as cellulose phthalate(Sepifilm, Pharmacoat), or polyvinylic of the OPADRY PVA or Sepifilm ECLtype, or saccharosic such as the sugar for coating of the Sepisperse DR,AS, AP or K types (coloured).

The tablets, whether coated or not, can in addition be coloured at thesurface or throughout, with mineral, vegetable or synthetic dyes (forexample lacquer with quinoline-yellow, or E 104 or iron oxides).

The proportions of the various constituents vary g to the nature of thetablet to be made.

The content of active ingredients can range from 0.3 to 1.5 mg for thenomegestrol acetate and from 0.3 to 3 mg for the free or esterifiedestradiol or for the conjugated equine estrogens. The dilution agentsrange from 20 to 75% of the total mass, the gliding agents from 0.1 to2% of the total mass, the compaction binding agents range from 2 to 20%,the polyvinylpyrrolidone from 0.5 to 15%, the disintegration agentsrange from 2 to 5.5% for cross-linked polyvinylpyrrolidone orcarboxymethyl starch, and from 2.0 to 3.0% for croscarmellose.

The quantities of lubrication agents vary from 0.1 to 3.0%, depending onthe type of agent.

The compositions according to the invention are intended to beadministered once per day. However, depending on the therapeutic needs,the administration may be divided (twice daily) or, on the contraryrepeated (two tablets per day).

The following examples illustrate the invention without limiting it inany way.

EXAMPLE 1 Examples of Formulations

The association of nomegestrol acetate and estradiol is presented in theform of plain or film-coated tablets.

The mixture of ingredients can either be compacted directly, or apreliminary estradiol mixture can be made into which the nomegestrolacetate and the other excipients are then incorporated in dry form. Thepreliminary estradiol mixture is made by dissolving the estradiol in analcoholic solution of microcrystalline cellulose, PVP and lactose,drying it, and then grinding and calibrating it. This process isadvantageous because tablets made from a preliminary estradiol mix havean estradiol dissolution profile which is appreciably better comparedwith tablets made by direct compaction.

The final mixture can contain from 1.5 to 5% of estradiol in povidone (5to 25%), microcrystalline cellulose (5 to 15%) and lactose (enough tomake up to 100%). It can be advantageous to introduce an anti-oxidantagent such as alpha-tocopherol or ascorbic acid during the preparationof the preliminary mix.

As an example, the following preliminary mix can be mentioned:

FORMULATIONS in mg/one tablet in % Estradiol 1.50 1.82 PVP K25 13.5016.36 Lactose 8195 60.00 72.73 Microcrystalline cellulose 7.50 9.09TOTAL DRY MIX 82.50 100.00

This preliminary mix is introduced into the final mixture to obtain atablet by direct compaction.

The finished tablets, uncoated, generally weigh 60 to 200 mg and havethe following overall formulation:

Formulations of the Coated Tablets

Composition in mg per tablet Estradiol (pre-mix, quantity sufficientfor) 0.3 to 3.0 Nomegestrol acetate 0.300 to 1.500 Colloidal silica0.400 to 2.000 Crospovidone 2.500 to 4.000 Lactose 60.000 to 80.000Cellulose 10.000 to 25.000 Stearic acid 0.900 to 3.000 Talc 0.450 to1.500

As examples, tablets can be mentioned which weigh 185 mg and have thefollowing formulas:

Example of the Formulation (UF=Unitary Formulation) of 185 Mg Tablets

UF mg per 1 tablet FORMULATION of 185 mg UF % Estradiol 1.500 0.811Nomegestrol acetate 0.625 0.338 Lactose 131.790 71.238 Cellulose (AvicelPH 101) 27.810 15.032 Povidone (K25) 13.500 7.297 Precirol (AT05) 2.7801.503 Colloidal silica (Aerosil 200) 1.000 0.540 Crospovidone(Polyplasdone XL) 6.000 3.243 TOTAL 185.00 100.000

Example of the Formulation (UF=Unitary Formulation) of 185 Mg Tablets

UF mg per 1 tablet FORMULATION of 185 mg UF % Estradiol 0.500 0.270Nomegestrol acetate 0.625 0.339 Lactose 136.787 73.934 Cellulose (AvicelPH 101) 32.813 17.736 Povidone (K25) 4.500 2.432 Precirol (AT05) 2.7751.500 Colloidal silica (Aerosil 200) 1.000 0.540 Crospovidone(Polyplasdone XL) 6.000 3.243 TOTAL 185.00 100.000

Example of the Formulation (UF=Unitary Formulation) of 120 Mg Tablets

UF mg per 1 tablet FORMULATION of 120 mg UF % Estradiol 1.500 1.250Nomegestrol acetate 1.250 1.042 Lactose 84.000 70.000 Cellulose (AvicelPH 101) 11.250 9.375 Povidone (K25) 13.500 11.250 Colloidal silica(Aerosil 200) 1.000 0.833 Crospovidone (Polyplasdone XL) 3.000 2.500Magnesium stearate 1.000 0.833 Talc 1.000 0.833 Stearic acid AC/50VG2.500 2.083 TOTAL 120.00 100.000

Example of the Formulation (UF=Unitary Formulation) of 120 Mg Tablets

UF mg per 1 tablet FORMULATION of 120 mg UF % Estradiol 0.500 0.417Nomegestrol acetate 0.625 0.521 Lactose 89.000 74.167 Cellulose (AvicelPH 101) 16.875 14.062 Povidone (K25) 4.500 3.750 Colloidal silica(Aerosil 200) 1.000 0.833 Crospovidone (Polyplasdone XL) 3.000 2.500Magnesium stearate 1.000 0.833 Talc 1.000 0.833 Stearic acid AC/50VG2.500 2.083 TOTAL 120.00 100.000

Example of the Formulation (UF=Unitary Formulation) of 80 Mg Tablets

UF mg per 1 tablet FORMULATION of 80 mg UF % Estradiol 0.500 0.625Nomegestrol acetate 0.625 0.781 Kollidon 25 4.500 5.625 Lactose M 59.73574.669 Cellulose (Avicel PH 101) 12.000 15.000 Crospovidone(Polyplasdone XL) 0.800 1.000 Talc 0.700 0.550 Colloidal silica (Aerosil200) 0.440 0.550 Magnesium stearate 0.700 0.875 TOTAL 80.000 100.000

Example of the Formulation (UF=Unitary Formulation) of 80 Mg Tablets

UF mg per 1 tablet FORMULATION of 80 mg UF % Estradiol 1.000 1.250Nomegestrol acetate 1.250 1.563 Kollidon 25 9.000 11.250 Lactose M54.110 67.637 Cellulose (Avicel PH 101) 12.000 15.000 Crospovidone(Polyplasdone XL) 0.800 1.000 Talc 0.700 0.875 Colloidal silica (Aerosil200) 0.440 0.550 Magnesium stearate 0.700 0.875 TOTAL 80.000 100.000

These tablets may be coated, for example with:

-   -   film-forming agents based on polyvinyl alcohol of the type        OPADRY PVA “moisture barrier” (polyvinyl alcohol, titanium        dioxide, purified talc, lecithin, xanthan gum, pigments,        lacquers),        or    -   film-forming agents based on cellulose of the type SEPIFILM L.P.        ([H.P.M.C. (hydroxypropylmethylcellulose)], microcrystalline        cellulose, stearic acid, pigments, lacquers).

EXAMPLE II Dissociation of the Antimitotic and Differentiating Effectsof Nomegestrol Acetate on Endometrial Cells

Menopausal women, whether naturally or as the result of surgery, weresubjected to a sequential estrogen-progestative therapy. From Day 1 toDay 12 they received 30 μg of ethinyl estradiol and then, from Day 13 toDay 22, the same dose of ethinyl estradiol associated with differentdoses of nomegestrol acetate or chlormadinone acetate. The doses were asfollows:

Nomegestrol 0.1 0.25 0.5 1 2.5 5 and 10 acetate (mg): Chlormadinone 0.10.5 1 2 5 and 10 acetate (mg):

The number of women was between 2 and 11, depending on the group. Therewas then a therapeutic pause of 7 days followed by a second treatmentcycle.

The parameters taken into account were as follows:

-   -   the interval before periods commenced after the therapy had been        interrupted, following the first and second treatment cycles;    -   the histological appearance of the endometrium recovered in a        biopsy carried out between Day 17 and Day 20 of the second        cycle.

The results showed that:

-   -   The interval before periods appeared is a function of the dose        and is similar for both products. The dose required for no        periods to appear before the end of the therapy is between 0.2        and 0.3 mg/day for both products (Table 1).    -   The transformation of the endometrium into a secretory        endometrium is total with both products from 1 mg/day upwards,        but decreases at the highest doses (10 mg/day).    -   The proliferation activity, expressed as the number of mitoses        in the glandular cells, seems more strongly inhibited by        nomegestrol acetate than by chlormadinone acetate. Mitosis no        longer takes place in women treated with a dose equal to or        higher than 0.5 mg/day of nomegestrol acetate, while mitosis is        still evident with a daily dose of 1 mg/day of chlormadinone        acetate (Table 2).

It can therefore be concluded that at the endometrial level, nomegestrolacetate and chlormadinone acetate are not comparable: the secretorytransformation activity is comparable but nomegestrol acetate ischaracterised by a very marked antimitotic and antiproliferative action.

TABLE 1 Interval before the appearance of periods (days) after thetherapy is discontinued Dose (mg/day) Progestative 0.1 0.25 0.5 1.0 2.02.5 5 10 Nomegestrol −0.5 ± 1.5 −0.5 ± 0.5 1.5 ± 0.5 2.7 ± 0.2 3.2 ± 0.24.3 ± 0.4 3.8 ± 0.8 acetate Chlormadinone −2.3 ± 0.5 2.0 ± 0.6 3.8 ± 0.33.8 ± 0.3 5.5 ± 0.5 5.5 ± 0.5 acetate

TABLE 2 Evaluation of the number of mitoses (% of section in whichmitoses were present) Dose (mg/day) 0.1 0.25 0.5 1 2 2.5 5 10 GlandsNomegestrol 50 50 0 0 0 0 0 30 acetate Chlormadinone 90 50 0 0 0 acetate

EXAMPLE III A Trial was Carried Out to Study the Effects on theEndometrium of the Continuous Combined Association of an Oral EstradiolDose Equivalent to 1.5 Mg and Various Doses of Nomegestrol Acetate

This consisted in the treatment for 6 consecutive months of 179 womenwho had been menopausal for at least 3 years, with 1.5 mg per day ofestradiol combined continuously with 4 different doses of nomegestrolacetate: 5 mg/day (n=47); 2.5 mg/day (n=42); 1.25 mg/day (n=43) and0.625 mg/day (n=47).

The impact of these four associations on the endometrium was evaluatedby recording the characteristics of genital bleeding, measuring thethickness of the endometrium by endovaginal echography before and at theend of the therapy, and by carrying out a biopsy of the endometriumbefore and at the end of the therapy.

The percentages of women who showed no genital bleeding at allthroughout the therapy were respectively 42.5-58.1-52.4 and 68.1%, withthe doses of 0.625-1.25-2.5 and 5 mg of nomegestrol acetate per day. Thepercentages observed are not statistically different between the groups,but the relation between the dose and the incidence of bleeding issignificant.

The tables attached indicate, for each nomegestrol acetate dose, theresults of the echographic examination and biopsy of the endometriumcarried out at the end of the 6 months of treatment.

At the end of the therapy, the mean thickness of the endometrium is notdifferent between the groups. The increase of the endometrial thicknessunder therapy is 0.39 mm on average with the smallest nomegestrolacetate dose. This thickening increases slightly as a function of dose,becoming 1.56 mm in the group of women who received 5 mg/day of theprogestative, but the relation between the variation of thickness andthe dose variation does not reach the threshold of statisticalsignificance.

The biopsies of the endometrium examined at the end of the trial showedno proliferative or hyperplasic appearance of the uterine mucosa. Thehighest percentage of secretory endometria was observed in the women whohad received the highest progestative dose; it decreased progressivelyand in a statistically significant way with the dose. In contrast, thehighest percentage of atrophic endometria was found at the lowestprogestative dose and this decreased as the dose increased.

These results are unexpected in the sense that they show that low dosesof nomegestrol acetate administered in continuous combination with anestrogen are capable of preventing the growth of the uterine mucosa andkeeping it in an atrophic condition, whereas, in contrast to higherdoses, they are insufficient to induce a secretory transformation of theendometrium.

Thus, this trial reveals a surprising decoupling of the anti-estrogeniceffect of nomegestrol acetate from its progestational effect, when it isadministered in continuous combination with estrogens.

The anti-estrogenic effect is preponderant since it is detectable whenthe progestative, administered continuously with an estrogen, is givenat low doses. These doses are insufficient to bring about secretorytransformations of the uterine mucosa. At higher doses and with the sametherapeutic scheme, the secretory effect predominates, though withoutallowing excessive proliferation of the endometrium.

TABLE I Endometrial thickness after 6 months of continuous treatmentwith several combined associations based on estradiol (2 mg of estradiolvalerate) and nomegestrol acetate (NOMAC) at various doses Doses ofNOMAC (mg/day) 0.625 1.25 2.5 5 (n = 35) (n = 33) (n = 34) (n = 41) Meanthickness 3.18 4.05 3.93 3.83 at the end of the (1.65) (3.75) (2.10)(2.72) treatment (mm) Mean thickness 0.39 1.12 1.36 1.57 increase underthe (1.67) (3.67) (1.54) (2.39) treatment (mm) ( ) = standard deviation

TABLE 2 Histological appearance of the endometrium after 6 month ofcontinuous treatment with several combined associations containingestradiol (2 mg of estradiol valerate) and nomegestrol acetate (NOMAC)at various doses Doses of NOMAC (mg/day) 0.625 1.25 2.5 5 (n = 32) (n =33) (n = 34) (n = 40) Absence of 5 10 3 3 endometrium (15.6) (30.3)(8.8) (7.5) Atrophic 19 10 8 3 endometrium (59.4) (30.3) (23.5) (7.5)Secretory 8 12 22 34 endometrium (25.0) (36.4) (64.7) (85.0) Polyps 0 11 0 (3.0) (2.9) ( ) = percentage In no case was the endometriumproliferative or hyperplasic.

1. Pharmaceutical hormone compositions characterised in that they areformed of a combined estrogen-progestative association intended for oraladministration, and they make possible the simultaneous administrationof an estrogenic compound at a dose ranging from 0.3 to 3 mg and aprogestative compound derived from 19-norprogesterone at a dose rangingfrom 0.3 to 1.5 mg, in association or in admixture with one or morenon-toxic, inert and pharmaceutically acceptable diluents. 2.Estrogen-progestative compositions according to claim 1, in which theestrogen is 17β-estradiol, whether free or esterified, or conjugatedequine estrogens.
 3. Estrogen-progestative compositions according toclaim 1, in which the estrogen is 17β-estradiol. 4.Estrogen-progestative compositions according to claim 1, in which theestrogen is an estradiol ester, such as estradiol valerate inparticular.
 5. Estrogen-progestative compositions according to claim 1,in which the estrogen consists of conjugated equine estrogens. 6.Estrogen-progestative compositions according to claim 1, in which thefree or esterified estrogen or a conjugated equine estrogen is presentin an amount ranging from 03 to 3 mg per unitary dose. 7.Estrogen-progestative compositions according to claim 1, in which theestradiol is present in the free form preferably in an amount of 0.5 to1.5 mg per unitary dose.
 8. Estrogen-progestative compositions accordingto claim 4, in which an estradiol ester is present, preferably in anamount of 1.5 to 2 mg per unitary dose.
 9. Estrogen-progestativecompositions according to claim 1, in which the conjugated equineestrogen is present preferably in an amount of 0.312 to 0.625 mg perunitary dose.
 10. Estrogen-progestative compositions according to claim1, in which the progestative is nomegestrol or one of its esters. 11.Estrogen-progestative compositions according to claim 10, in which theprogestative is nomegestrol acetate.
 12. Estrogen-progestativecompositions according to claims 10 and 11, in which the nomegestrolacetate is present in an amount ranging from 0.3 to 1.5 mg per unitarydose.
 13. Estrogen-progestative compositions according to claims 10 to12, in which the nomegestrol acetate is present in an amount between0.625 and 1.25 mg per unitary dose.
 14. A process for the preparation ofnew estrogen-progestative compositions according to claim 1, in whichthe estrogenic active ingredient and the progestational activeingredient are admixed or combined with one or more inert, non-toxic andpharmaceutically acceptable diluents.
 15. A method of using theestrogen-progestative mixture according to claim 1, to produce amedicament intended for treating estrogen deficiencies in menopausalwomen in need thereof.
 16. A method of using the estrogen-progestativemixture according to claim 1, for producing a medicament intended toprevent osteoporosis and cardiovascular disorders in menopausal women inneed thereof.
 17. A method of using the estrogen-progestative mixtureaccording to claim 1, to produce a medicament intended for continuous orintermittent administration in need thereof.